Dendritic Cell-Associated C-Type Lectins

描述（由申请人提供）：令人惊讶的是，关于抗原（Ags）如何进入免疫系统并诱导B细胞产生持续水平的中和抗体（Abs），从而保护我们免受致命病毒和细菌的侵害，我们知之甚少。该提案的主要目标是阐明长寿命记忆B细胞的发展所需的过程，这是在抗原被脾树突状细胞（DC）亚群摄取后启动的。我们将确定Ag靶向边缘区（MZ）DC和浆细胞样DC（pDC）亚群诱导记忆B细胞和体液免疫的机制。我们的目标是：1。目的：研究如何通过将抗原偶联到人CD4、BDCA 2和仅在pDC上表达BDCA 2的转基因（Tg）小鼠的特异性单克隆抗体（mAb）来体内靶向浆细胞样DC，从而调节CD4和CD8 T细胞和体液免疫应答。2.确定BDCA 2信号是否以及如何抑制pDC体内I型IFN的产生，以及这种抑制是否可以改变狼疮样自身免疫性疾病的病程。和3.确定体内如何通过将Ag靶向MZ DC产生滤泡外Ab应答，并确定哪些信号将通过MZ DC靶向诱导的滤泡外Ab应答转变为导致GC形成和长寿命、高亲和力Ab的免疫应答。我们将研究MHC II类和CD22在MZ DC为基础的Ag靶向中的作用，并表征MZ DC激活滤泡外TEFH细胞所需的分子过程。这些研究可能会导致新的见解如何诱导和调节免疫记忆，特别是体液免疫。它们还可以通过帮助定义导致B细胞中的体细胞突变和亲和力成熟的体内途径来帮助推进B细胞生物学领域。拟议的研究还可能导致新的Ag靶向技术，用于创建有效的疫苗，诱导针对重要病原体如H5N1流感大流行性流感，艾滋病毒和丙型肝炎病毒的强中和抗体反应。

DESCRIPTION (provided by applicant): Surprisingly little is known about how antigens (Ags) enter the immune system and induce B cells to produce sustained levels of neutralizing antibodies (Abs), which protect us against deadly viruses and bacteria. The major goal of this proposal is to elucidate processes required for the development of long-lived memory B cells, which are initiated after Ags are taken up by splenic dendritic cell (DC) subsets. We will define the mechanisms by which Ag targeting to marginal zone (MZ) DC and plasmacytoid DC (pDC) subsets induce the development of memory B cells and humoral immunity. Our Aims are: 1. To define how to regulate CD4 and CD8 T cell and humoral immune responses by targeting Ags to plasmacytoid DCs in vivo using Ags coupled to monoclonal antibodies (mAbs) specific for the human CLR, BDCA2 and transgenic (Tg) mice expressing BDCA2 only on pDCs. 2. To define if and how BDCA2 signaling inhibits type I IFN production by pDCs in vivo and whether this inhibition can alter the course of a lupus-like autoimmune disease. And 3. To define how extrafollicular Ab responses are generated by targeting Ags to MZ DCs in vivo and define what signals shift extrafollicular Ab responses induced via MZ DC targeting into an immune response leading to GC formation and long-lived, high-affinity Abs. We will investigate the role of MHC class II and CD22 in MZ DC-based Ag targeting and characterize the molecular processes required for MZ DCs to activate extrafollicular TEFH cells. These studies may lead to new insights into how to induce and regulate immunologic memory, and in particular humoral immunity. They may also help advance the field of B cell biology by helping to define the in vivo pathways leading to somatic mutation in B cells and affinity maturation. The proposed studies also may lead to new Ag targeting technology useful for the creation of effective vaccines which induce strong neutralizing antibody responses against important pathogens like H5N1 pandemic FLU, HIV, and hepatitis C viruses.